Neuroprotective strategies in seizure-induced damage

描述（由申请人提供）：2-雌二醇（EB）在几种神经退行性疾病中具有神经保护作用。此外，EB可以防止癫痫持续状态（SE）诱导的海马齿状回门部神经元损伤。这种保护作用只发生在雌性老鼠身上，而不在雄性老鼠身上。初步研究表明，神经保护与通过配对脉冲刺激确定的齿状回晚期抑制增加有关。由于这一发现表明缓慢的，g蛋白连接的神经递质系统的参与，代谢性谷氨酸受体（mGluR）和神经肽Y （NPY）进行了研究。NPY和mGlu受体似乎都参与其中并相互补充。当齿状回过滤来自内嗅皮层的活动时，EB对门门神经元的神经保护作用可能与增强的过滤特征有关。这一提议的主要假设是，在女性中，EB增加了齿状回的抑制。denatate gyrus抑制的增加是由NPY和mGluR系统介导的，并导致海马对传入的癫痫活动的过滤增强，从而对hilal神经元产生神经保护作用。具体的目的是确定：是否1A；EB增加齿状回抑制。1 b。eb诱导的抑制增加涉及NPY和mGlu受体。1 c。EB同时影响前馈和反馈抑制，1D。EB诱导NPY和mGluR表达变化。2 a。EB通过激活NPY和mGlu受体阻止癫痫样活动通过齿状回扩散。2 b。EB改变齿状颗粒细胞输入谷氨酸释放及其内在特性。3. 阻断NPY和mGlu受体对eb诱导的肝门损伤的神经保护作用。各组包括经EB、孕酮、EB+孕酮或油处理的去性腺雌性大鼠和经EB或油处理的性腺完整雌性大鼠。方法包括内鼻皮质-海马联合切片的体外研究，配对脉冲刺激，使用特异性NPY和mGlu拮抗剂，细胞内记录，免疫组织化学，组织学，体视细胞计数，体内诱导SE以及阻断NPY和mGlu受体。本研究提出了EB在海马中与NPY和mGluR相互作用有关的新机制。我们的研究结果还将为理解抑郁/焦虑、压力处理、记忆和认知等过程的性别特异性表达提供见解。2-雌二醇对包括癫痫引起的海马损伤在内的几种神经退行性疾病具有神经保护作用。本研究的重点是确定2-雌二醇诱导的海马神经保护机制。我们发现，2-雌二醇的管理诱导神经肽Y的表达，一种抑制和神经保护肽，在齿状回。这个结构是海马体的入口，具有过滤功能。我们将研究这种抑制性神经肽的增加如何增强齿状回对诸如癫痫发作等传入活动的过滤，以及这种增加的过滤如何影响癫痫诱发的海马损伤。

DESCRIPTION (provided by applicant): 2-Estradiol (EB) has neuroprotective effects in several neurodegenerative diseases. Additionally, EB protects against status epilepticus (SE)-induced neuronal damage in the hilus of the hippocampal dentate gyrus. This protection occurs only in female but not in male rats. Preliminary studies have shown that neuroprotection is associated with increased late phase inhibition in the dentate gyrus determined by paired pulse stimulation. As this finding suggests participation of slow, G-protein linked neurotransmitter systems, metabotropic glutamate receptors (mGluR) and neuropeptide Y (NPY) were investigated. Both NPY and mGlu receptors seem to be involved and complement each other. As dentate gyrus filters the activity coming from the entorhinal cortex, neuroprotective effects of EB on hilar neurons may be associated with enhanced filtering features. Main hypothesis of this proposal is that in females, EB increases inhibition in the dentate gyrus. The increase in the denatate gyrus inhibition is mediated by the NPY and mGluR systems and results in enhanced filtering of incoming seizure activity to the hippocampus leading thus to neuroprotective effects on hilar neurons. Specific aims are to determine: Whether 1A. EB increases dentate gyrus inhibition. 1B. EB-induced increase in inhibition involves NPY and mGlu receptors. 1C. EB affects both feed-forward and feed-back inhibition, 1D. EB induces changes in NPY and mGluR expression. 2A. EB prevents spread of epileptiform activity through the dentate gyrus via activation of NPY and mGlu receptors. 2B. EB changes glutamate release at the inputs of dentate granule cells and their intrinsic properties. 3. The effects of blockade of NPY and mGlu receptors on EB-induced neuroprotection against SE-induced hilar damage. Groups include gonadectomized female rats treated with EB, progesterone, EB+progesterone or oil, and also gonadally intact female rats treated with EB or oil. Methods include in vitro studies in combined entorhinal cortex-hippocampus slices, paired pulse stimulation, use of specific NPY and mGluR antagonists, intracellular recordings, immunohistochemistry, histology, stereological cell counting, in vivo induction of SE as well as blockade of NPY and mGlu receptors. Here, novel mechanisms of EB action in the hippocampus involving NPY and mGluR interactions are proposed. The findings from our studies will also bring insights into understanding of gender-specific expression of such processes as depression/anxiety, stress processing, memory, and cognition.2-Estradiol has neuroprotective effects in several neurodegenerative diseases including the seizure-induced hippocampal damage. This proposal is focused on determining the mechanisms involved in 2-estradiol-induced neuroprotection in the hippocampus. We found that administration of 2-estradiol induces expression of neuropeptide Y, an inhibitory and neuroprotective peptide, in the dentate gyrus. This structure is an entry to the hippocampus proper and has filtering function. We will investigate how this increase of inhibitory neuropeptide will enhance the dentate gyrus filtering of incoming activity such as seizures and how this increased filtering can affect seizure-induced hippocampal damage.